Apolipoprotein (apo) A-I, the major protein component of HDL, and apo E, a protein component of VLDL, are antiatherogenic. While apo A-I inhibits atherosclerosis without changing plasma cholesterol levels, apo E can reduce the plasma levels of atherogenic lipoproteins. Analogous to the observation that the lipid cross-sectional shapes can regulate membrane properties, we predicted and have shown that the cross-sectional shapes of class A and class L peptides are partially responsible for properties of a lipid surface with which they interact. We showed that class A amphipathic-helical peptides inhibit atherosclerosis without changing plasma cholesterol levels and that Arg-containing class L peptides enhance the uptake of atherogenic lipoproteins in cell culture and in dyslipidemic mouse models. We propose to test the hypothesis that specific alterations of the surface of atherogenic lipoproteins inhibit(s) atherosclerosis by 1) accelerating reverse cholesterol transport (RCT) or 2) inhibiting the formation of oxidized LDL or 3) enhancing the hepatic uptake of atherogenic lipoproteins. Two specific aims to test this are: 1.To identify the determinants and mechanisms by which class A peptides inhibit atherosclerosis. a) Physical chemical properties which correlate to their lipoprotein association. b) Role in RCT: cholesterol efflux rates and the contribution of SR-BI and ABC A1 in peptide-mediated cholesterol transfer. c) Role in inhibition of formation of atherogenic lipoproteins. d) Effect of peptide analogs to inhibit the generation of inflammatory molecules; 2. Studies of peptide analogs based on the reciprocal wedge hypothesis: design of Arg-rich class L amphipathic helical peptides for enhanced hepatic uptake of atherogenic lipoproteins. a) Correlate physical-chemical properties with atherogenic lipoprotein association. b) Determine the mechanisms of enhanced lipoprotein uptake. c) Identify the specific receptors for the peptide-lipoprotein uptake d) Peptide-mediated changes in expression of apolipoproteins in HepG2 cells. Studies described in this project will increase our current limited knowledge on how surface alterations of lipoproteins influence the metabolism of cholesterol and will generate a new database, which will facilitate designing small molecules that can be used therapeutically to ameliorate atherosclerosis.